Renin is a natural enzyme which is released into the blood from the kidney. It cleaves its natural substrate, angiotensinogen, releasing decapeptide, angiotensin I. This is in turn cleaved by converting enzyme in the lung, kidney and other tissues to an octapeptide, angiotensin II. Angiotensin II raises blood pressure both directly by causing arteriolar constriction and indirectly by stimulating release of the sodium-retaining hormone aldosterone from the adrenal gland causing a rise in extracellular fluid volume. Inhibitors of renin have been sought as agents for control of hypertension, congestive heart failure, and hyperaldosteronism.
European Application Number EP-229667 covers renin inhibiting peptidyl-amino-diols of formula ##STR1## wherein A is a substituent; W is C.dbd.O or CHOH; U is CH.sub.2 or NR.sub.2 ; R.sub.1 is lower alkyl, cycloalkylmethyl, benzyl, 4-methoxybenzyl, halobenzyl, (1-naphthyl)methyl, (2-naphthyl)methyl, (4-imidazoyl)methyl, .alpha., .alpha.-dimethylbenzyl, 1-benzyloxyethyl, phenethyl, phenoxy, thiophenoxy or anilino; R.sub.3 is lower alkyl, [(alkoxy)alkoxy]alkyl, (thioalkoxy)alkyl, lower alkenyl, benzyl or heterocyclic ring substituted methyl; R.sub.4 is lower alkyl, cycloalkylmethyl or benzyl; R.sub.5 is vinyl, formyl, hydroxymethyl or hydrogen; R.sub.7 is hydrogen or lower alkyl; R.sub.8 and R.sub.9 are independently selected from OH and NH.sub.2 ; and R.sub.6 is hydrogen, lower alkyl, vinyl or arylalkyl.
European Application 186,977 covers certain renin-inhibitory peptides of formula ##STR2## wherein m is 0 or 1 and R.sup.1 to R.sup.3 are a variety of organic groups. The R.sup.3 covers many groups.
Structurally the positions of the various amino acids (amino acid mimics) of the compounds of the instant invention may be designated by reference to the octapeptide which is the minimal angiotensinogen sequence cleaved by renin, namely: ##STR3##
A designation for the compounds of this invention is illustrated below. The CAD is considered to occupy the P.sub.1 -P.sub.1 ' positions. For example ##STR4##
The present invention concerns novel compounds which inhibit renin. It also concerns pharmaceutical compositions containing these novel peptides, methods of treating renin-associated hypertension, congestive heart failure, glaucoma, and hyperaldosteronism, as well as the use of the compounds as diagnostic tools, and the methods for preparing the compounds.
Since HIV protease, like renin, is an aspartyl protease, these compounds can also be used to treat diseases caused by retroviruses including HTLV-I and -III.